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Role of central endpoint adjudication and challenges in trials on neonatal sepsis-a case of ProSPoNS trial
Anju Pradhan Sinha1, Dilip Raja2, Kamlesh S Mahajan3
1Division of Reproductive, Child Health and Nutrition (RCN), Indian Council of Medical Research (ICMR) Headquarters, V Ramalingaswami Bhawan, Ansari Nagar, New Delhi, Delhi, 110029, India. apradhandr@gmail.com.
Insights
The ProSPoNS trial clarified its primary outcome to "physician diagnosed sepsis" to improve consistency in assessing neonatal sepsis prevention in vulnerable infants. This ensures accurate data collection for probiotic intervention effectiveness.
Area of Science:
- Neonatal Health
- Clinical Trial Methodology
- Infectious Disease Prevention
Background:
- Neonatal mortality decline in India lags behind infant mortality, highlighting the need for interventions targeting Sustainable Development Goal-3.
- Neonatal sepsis poses a significant threat to high-risk, low birth weight infants.
- Probiotic supplementation is being investigated as a novel strategy to prevent neonatal sepsis.
Purpose of the Study:
- To establish a Central Endpoint Adjudication Committee (CEAC) for the ProSPoNS trial.
- To clarify and unify the primary study outcome for accurate assessment of neonatal sepsis.
- To ensure methodological transparency and consistency in a multicentric clinical trial.
Main Methods:
- The ProSPoNS trial investigators established a CEAC as an addendum to the published protocol.
- The CEAC will adjudicate the primary outcome, "physician diagnosed sepsis," which encompasses sepsis/PSBI.
- Four criteria will be used by the CEAC: blood culture status, sepsis screen status, PSBI/non-PSBI signs and symptoms, and clinical course.
Main Results:
- The investigators unanimously agreed to define "physician diagnosed sepsis" as the primary outcome, aligning hypothesis, objective, and sample size.
- This clarification maintains consistency with the original approved study protocol (Version 3.1).
- The CEAC's role ensures consistency and accuracy in outcome assessment for this complex trial.
Conclusions:
- Establishing a CEAC is crucial for standardizing outcome assessment in multicentric clinical trials.
- Clarifying the primary outcome "physician diagnosed sepsis" enhances the reliability of the ProSPoNS trial findings.
- This methodological refinement supports the goal of reducing neonatal mortality through targeted interventions.
Abstract:
Despite progress in reducing the infant mortality in India, the neonatal mortality decline has been slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming to prevent neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention includes probiotic supplementation. This article communicates the decision by the ProSPoNS trial investigators to establish a Central Endpoint Adjudication Committee (CEAC) as an addendum to the protocol published in Trials in 2021 for the purpose of clarifying the primary outcome. In the published protocol, the study hypothesis and primary objective are based on "sepsis," the primary outcome has been specified as sepsis/PSBI, whereas the sample size estimation was performed based on the "physician diagnosed sepsis." To align all the three above, the investigators meeting, held on 17th-18th August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that "physician diagnosed sepsis" is the primary study outcome which includes sepsis/PSBI. The CEAC, chaired by an external subject expert and members including trial statistician, a microbiologist, and all site principal investigators will employ four criteria to determine "physician diagnosed sepsis": (1) blood culture status, (2) sepsis screen status, (3) PSBI/non-PSBI signs and symptoms, and (4) the clinical course for each sickness event. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No. 5/7/915/2012 version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. The decision to utilize the guidance of a CEAC is recommended as the gold standard in multicentric complex clinical trials to achieve consistency and accuracy in assessment of outcomes.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.
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